The invention relates generally to pharmaceutical compositions and specifically to improved radiological contrast composition for the prevention of toxic side effects associated with the administration of certain iodo-benzamido-glucopyranose x-ray contrast media.
Metrizamide, 2-[3-Acetamido-2,4,6-triiodo-5-(N-methylacetamido) benzamido]-2-deoxy-D-glucopyranose, is widely used as a radiological contrast agent for cerbrospinal myelography. Although metrizamide and chemically related compounds have been regarded as the safest myelographic materials commercially available, temporary confusional state and EEG deterioration occur in about one-third of patients treated. More serious but less frequent central nervous system effects include asterixis, visual, auditory or speech disturbances, grand mal seizures and aseptic meningitis syndrome. These side effects have been recognized for many years, but in 1979 and 1980 several reports of fairly large series of patients with frequent confusion and perceptual aberrations appeared.
Efforts to minimize central nervous system complication and irritation induced by metrizamide and chemically related radiological contrast agents have heretofore involved using the minimum concentration of the contrast agent required for satisfactory contrast; positioning the patient with his head higher than the highest level of the spine; avoiding intracranial introduction of a bolus of contrast composition; administering a small amount of the contrast agent in cervical puncture for studies of the upper spine; injecting the bolus slowly to avoid excess mixing and rapid diffusion in higher cephalad positions; and avoiding abrupt patient movement to prevent excessive mixing of bolus with cerebral spinal fluid. All these manipulative effects are intended to reduce the amount of contrast agent that diffuses to the brain.
Rather than relying on indirect manipulative steps to avoid contrast agent diffusion to brain, there is a need for an inexpensive, reliable, direct mechanism to avoid central nervous system complications induced by the iodo-benzamido-glucopyranose x-ray contrast agents. Following intense pharmacological research into the biochemical activity of the contrast agents, typified by metrizamide, Applicant has discovered that such compounds interfere with glycolysis metabolism in the brain. Specifically, Applicant has demonstrated that metrizamide competes with glucose to inhibit hexokinase activity [see "Competitive Inhibition of Rat Brain Hexokinase by 2-Deoxyglucose, Glucosamine, and Metrizamide," J. Neurochemistry 37: 1000 (1981)]. This interference with the utilization of glucose, which normally serves as the obligatory energy source in the brain, may explain some of the depressive effects of intrathecally administered metrizamide and related compounds.